Oncogenic mutations in Ras-encoding genes are found in approximately 30% of all tumors and are most prevalent in carcinomas of the pancreas, colon, lung, and bladder. These mutations have profound effects on proliferation, cell survival, and tumor invasion. Ras orchestrates these events by activating downstream effector pathways that regulate actin reorganization and gene expression.
Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive malignancy with a dismal long term prognosis. The disease exhibits a median survival of less than 6 months and a 5-year survival rate of 3-5% (Maitra et al., “Pancreatic Cancer,” Annu. Rev. Pathol. 3:157-188 (2008) and Shi et al., “Sensitive and Quantitative Detection of KRAS2 Gene Mutations in Pancreatic Duct Juice Differentiates Patients with Pancreatic Cancer from Chronic Pancreatitis, Potential for Early Detection,” Cancer Biol. Ther. 7:353-360 (2008)). PDA evolves through a series of histopathological changes, referred to as pancreatic intraepithelial neoplasia (PanIN), accompanied by a recurrent pattern of genetic lesions the earliest and most ubiquitous of which is oncogenic activation of Kras (Maitra et al., “Pancreatic Cancer,” Annu. Rev. Pathol. 3:157-188 (2008) and Shi et al., “Sensitive and Quantitative Detection of KRAS2 Gene Mutations in Pancreatic Duct Juice Differentiates Patients with Pancreatic Cancer from Chronic Pancreatitis, Potential for Early Detection,” Cancer Biol. Ther. 7:353-360 (2008)). The essential role of oncogenic Kras in the pathogenesis of PDA is indicated by several genetically engineered mouse models where conditional expression of the mutated allele of Kras in the pancreas is necessary and/or sufficient to drive disease progression from the early preinvasive stage to a malignant stage (Hingorani et al., “Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse,” Cancer Cell 4:437-450 (2003); Hingorani et al., “Trp53R172H And KrasG12D Cooperate to Promote Chromosomal Instability and Widely Metastatic Pancreatic Ductal Adenocarcinoma in Mice,” Cancer Cell 7:469-483 (2005) and Seidler et al., “A Cre-Loxp-Based Mouse Model for Conditional Somatic Gene Expression and Knockdown In Vivo by Using Avian Retroviral Vectors,” Proc. Natl. Acad. Sci. U.S.A. 105:10137-10142 (2008)). Though the mechanisms by which oncogenic Kras contributes to the genesis and progression of PDA have not been fully elucidated, the proliferative and survival advantage conferred on epithelial cells by the expression of oncogenic Kras has been clearly implicated (Lee et al., “Oncogenic Kras Suppresses Inflammation-Associated Senescence of Pancreatic Ductal Cells,” Cancer Cell 18:448-458 (2010)).
In addition to the well-documented molecular and histological alterations exhibited by the tumor cells themselves as well as their pre-neoplastic precursors, a hallmark of PDA is an extensive stromal remodeling, the most prominent features of which are the recruitment of inflammatory and mesenchymal cells and fibrotic replacement of the pancreatic parenchyma (Chu et al., “Stromal Biology of Pancreatic Cancer,” J. Cell Biochem. 101:887-907 (2007) and Maitra et al., “Pancreatic Cancer,” Annu. Rev. Pathol. 3:157-188 (2008)). Strikingly, histological assessment of pancreata of afflicted human patients or mice engineered to express oncogenic Kras in the epithelial compartment of the pancreas reveal that even early stages of PanIN are associated with a stromal reaction which is characterized by a robust desmoplastic response and recruitment of immune cells (Chu et al., “Stromal Biology of Pancreatic Cancer,” J. Cell Biochem. 101:887-907 (2007) and Clark et al., “Dynamics of the Immune Reaction to Pancreatic Cancer From Inception to Invasion,” Cancer Res. 67:9518-9527 (2007)). The precise role played by the PanIN-associated stroma in PDA development has not been established. Based on the composition of the immune infiltrates surrounding the PanINs it has been proposed that the stromal constituents around PanINs form an inflammatory and immune suppressive environment thereby allowing the precursor lesion to escape immune surveillance (Clark et al., “Immunosurveillance of Pancreatic Adenocarcinoma: Insights From Genetically Engineered Mouse Models Of Cancer,” Cancer Lett. 279:1-7 (2009)). Consistent with this idea, studies in both humans and mice have demonstrated a dampened adaptive immune response accompanying the formation of oncogenic Ras-driven cancers (Clark et al., “Immunosurveillance of Pancreatic Adenocarcinoma: Insights From Genetically Engineered Mouse Models Of Cancer,” Cancer Lett. 279:1-7 (2009); DuPage et al., “Endogenous T Cell Responses to Antigens Expressed in Lung Adenocarcinomas Delay Malignant Tumor Progression,” Cancer Cell 19:72-85 (2011); Fossum et al., “CD8+ T Cells From a Patient with Colon Carcinoma, Specific for a Mutant P21-Ras-Derived Peptide (Gly13-->Asp), are Cytotoxic Towards a Carcinoma Cell Line Harbouring the Same Mutation,” Cancer Immunol. Immunother. 40:165-172 (1995); Gjertsen et al., “Mutated Ras Peptides as Vaccines in Immunotherapy of Cancer,” Vox Sang 74(Suppl 2):489-495 (1998); Kubuschok et al., “Naturally Occurring T-Cell Response Against Mutated P21 Ras Oncoprotein in Pancreatic Cancer,” Clin. Cancer Res. 12:1365-1372 (2006); Qin et al., “CD4+T-Cell Immunity to Mutated Ras Protein in Pancreatic and Colon Cancer Patients,” Cancer Res. 55:2984-2987 (1995); and Weijzen et al., “Modulation of The Immune Response and Tumor Growth by Activated Ras,” Leukemia 13:502-513 (1999)). Moreover, there is growing evidence that targeting the tumor immune microenvironment may provide an effective therapeutic strategy (Quezada et al., “Shifting the Equilibrium in Cancer Immunoediting: From Tumor Tolerance to Eradication,” Immunol. Rev. 241:104-118 (2011)).
The present invention is directed to overcoming these and other deficiencies in the art.